(E-162) Sex Differences in Murine Myocardial Infarction using 4D Ultrasound and Regional Mass Spectrometry Imaging Analysis

Introduction::

Cardiovascular disease (CVD), including myocardial infarction (MI), is the leading cause of death worldwide for both sexes. MI occurs when blood flow to the myocardium is obstructed, often by an occlusion of the coronary artery. The infarcted region becomes stiff and fibrous as healthy myocytes are replaced by scar tissue, and the heart remodels to compensate. Dilation and wall thinning in the ventricle during the remodeling process can lead to heart failure. These physiological changes are accompanied by pathological changes in the tissue, including altered lipid metabolism. Sex differences in the mechanisms of myocardial infarction and cardiac remodeling exist but are poorly understood, leading to sex-based discrepancies in diagnosis and prognosis. In this study, we seek to develop a better understanding of the physiological and pathological sex differences that govern the heart’s adaptation to injury and progression to heart failure using a mouse model of MI. We hypothesize that female mice will show functional metrics corresponding to more negative cardiac outcomes when compared to males. 

Materials and Methods::

We induced MI in a mouse model using permanent ligation of the left coronary artery (LCA) in age-matched males (n=7) and females (n=8). We then imaged the left ventricle of the heart using 2 and 4-dimensional ultrasound (4DUS) prior to MI and at days 1, 3, 5, 7, 14, and 28 following the infarct. Using images at these timepoints, we then calculated metrics of left ventricular function. At day 28, the animals were sacrificed, followed by removal of the heart. These hearts were sectioned, sprayed with a matrix, and analyzed with matrix-assisted laser desorption ionization (MALDI) mass spectrometry imaging (MSI) to spatially and quantitatively identify the lipidomic and metabolomic makeup of the myocardial tissue. Following MSI, the tissue will undergo histology to verify infarct areas.

Results, Conclusions, and Discussions::

Preliminary results describing days 0-7 of initial male (n=3) and female (n=5) groups show promising trends, and we will be expanding this dataset with groups currently in progress. There was no statistically significant difference between male and female survival rates or strain-mapped infarct size, which may suggest that, in these mice, variation in surgery performance did not confound sex comparison of functional metrics. Overall, sex difference in ejection fraction (EF) approached significance with males maintaining higher EF post-surgery when compared to females. There was a statistically significant sex difference in initial end diastolic volume (EDV), and when EDV data was normalized for initial values, EDV sex difference was significant at days 1 and 3, suggesting that female mice underwent more drastic dilation than males. MSI and histology results are forthcoming.

These results suggest that, with similar surgery survival rate and infarct size progression, females suffer more rapid functional deterioration and more severe left ventricular remodeling than their male counterparts. More severe remodeling in female hearts may be explained by a need for female hearts to remodel during pregnancy. Consequently, estrogen is known to have cardioprotective effects, guarding against CVD-related morbidity and mortality in reproductive aged females (Ichael et al., 1999). Future work may include an aged, ovariectomized female group to model post-menopausal estrogen deficiency and its effects on MI and cardiac remodeling. Our results and this methodology can likely be used to inform further studies aimed at examining sex differences in other instances of CVD.

Acknowledgements (Optional): :

References (Optional): : Ichael, M., et al. (1999). The Protective Effects of Estrogen on the Cardiovascular System. Mechanisms of Disease, 340, 1801.